Publications by authors named "Shiwen Xu"

158 Publications

Selective deletion of connective tissue growth factor attenuates experimentally-induced pulmonary fibrosis and pulmonary arterial hypertension.

Int J Biochem Cell Biol 2021 Mar 1;134:105961. Epub 2021 Mar 1.

Centre for Rheumatology and Connective Tissue Disease, Department of Inflammation, Division of Medicine, University College London, London, NW3 2PF, UK.

Connective tissue growth factor (CTGF, CCN2) is a matricellular protein which plays key roles in normal mammalian development and in tissue homeostasis and repair. In pathological conditions, dysregulated CCN2 has been associated with cancer, cardiovascular disease, and tissue fibrosis. In this study, genetic manipulation of the CCN2 gene was employed to investigate the role of CCN2 expression in vitro and in experimentally-induced models of pulmonary fibrosis and pulmonary arterial hypertension (PAH). Knocking down CCN2 using siRNA reduced expression of pro-fibrotic markers (fibronectin p < 0.01, collagen type I p < 0.05, α-SMA p < 0.0001, TIMP-1 p < 0.05 and IL-6 p < 0.05) in TGF-β-treated lung fibroblasts derived from systemic sclerosis patients. In vivo studies were performed in mice using a conditional gene deletion strategy targeting CCN2 in a fibroblast-specific and time-dependent manner in two models of lung disease. CCN2 deletion significantly reduced pulmonary interstitial scarring and fibrosis following bleomycin-instillation, as assessed by fibrotic scores (wildtype bleomycin 3.733 ± 0.2667 vs CCN2 knockout (KO) bleomycin 4.917 ± 0.3436, p < 0.05) and micro-CT. In the well-established chronic hypoxia/Sugen model of pulmonary hypertension, CCN2 gene deletion resulted in a significant decrease in pulmonary vessel remodelling, less right ventricular hypertrophy and a reduction in the haemodynamic measurements characteristic of PAH (RVSP and RV/LV + S were significantly reduced (p < 0.05) in CCN2 KO compared to WT mice in hypoxic/SU5416 conditions). These results support a prominent role for CCN2 in pulmonary fibrosis and in vessel remodelling associated with PAH. Therefore, therapeutics aimed at blocking CCN2 function are likely to benefit several forms of severe lung disease.
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http://dx.doi.org/10.1016/j.biocel.2021.105961DOI Listing
March 2021

Cadmium exposure induces TNF-α-mediated necroptosis via FPR2/TGF-β/NF-κB pathway in swine myocardium.

Toxicology 2021 Apr 21;453:152733. Epub 2021 Feb 21.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China. Electronic address:

Cadmium (Cd) is one common environmental pollutant with systemic toxicity. Lipoxin A4 (LXA4) can regulate transforming growth factor-β (TGF-β) pathway and alleviate tissue injury via binding to formyl peptide receptor 2 (FPR2). The activation of nuclear factor-κB (NF-κB) pathway can promote the occurence of necroptosis. However, whether Cd exposure induces necroptosis in swine myocardium and the role of FPR2/TGF-β/NF-κB pathway in this process are unclear. Hence, we established Cd-exposed swine myocardial injury model by feeding a CdCl added diet (20 mg Cd/kg diet). Hematoxylin-eosin (H&E) staining was used to observe the morphological changes, and inductively coupled plasma mass spectrometry (ICP-MS) was performed to detect the levels of ion elements in myocardium. We further detected LXA4 and its receptor FPR2, TGF-β, Nrf2, NF-κB pathway and necroptosis related-genes expressions by RT-PCR and western blot. The results showed that Cd exposure induced necrotic cell death and ion homeostasis imbalance in swine myocardium. Moreover, Cd exposure increased the LXA4 content, inhibited the FPR2 expression, activated TGF-β pathway and suppressed Nrf2 pathway, activating the NF-κB pathway. In addition, Cd exposure increased the expressions of necroptosis related-genes TNF-α, TNFR1, RIP1, RIP3 and MLKL. It indicated Cd exposure induced necroptosis via FPR2/TGF-β/NF-κB pathway, revealing the potential mechanism of Cd-induced cardiotoxicity in swine myocardium.
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http://dx.doi.org/10.1016/j.tox.2021.152733DOI Listing
April 2021

Cadmium exposure induces mitochondrial pathway apoptosis in swine myocardium through xenobiotic receptors-mediated CYP450s activation.

J Inorg Biochem 2021 Apr 2;217:111361. Epub 2021 Feb 2.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China. Electronic address:

Cadmium (Cd) pollution has become an important public and environmental health issue. Xenobiotic receptors (XRs, aryl hydrocarbon receptor, AHR; constitutive androstane receptor, CAR; pregnane X receptor, PXR) modulate downstream cytochrome P450 enzymes (CYP450s) expression to metabolize xenobiotics and environmental contaminants. However, the underlying mechanisms of cardiotoxicity induced by Cd(II) in swine and the roles of XRs and CYP450s remain poorly understood. In this study, the cardiotoxicity of Cd(II) was investigated by establishing a Cd(II)-exposed swine model (CdCl, 20 mg Cd/Kg diet). Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) assay and transmission electron microscope were used to observe the apoptosis. Antioxidant capacity was evaluated by free radicals contents and antioxidant enzymes activities. RT-PCR and western blot were used to measure the expression of XRs, CYP450s and apoptosis-related genes. Our results revealed that Cd(II) exposure activated the XRs and increased the CYP450s expression, contributing to the production of reactive oxygen species (ROS). Cd(II) exposure restrained the antioxidant capacity, causing oxidative stress. Moreover, mitogen-activated protein kinase (MAPK) pathway including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38 mitogen-activated protein kinase (P38) was activated, triggering the mitochondrial apoptotic pathway. In brief, we concluded that Cd(II) caused mitochondrial pathway apoptosis in swine myocardium via the oxidative stress-MAPK pathway, and XRs-mediated CYP450s expression might participate in this process through promoting the ROS.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111361DOI Listing
April 2021

Hydrogen sulfide of air induces macrophage extracellular traps to aggravate inflammatory injury via the regulation of miR-15b-5p on MAPK and insulin signals in trachea of chickens.

Sci Total Environ 2021 Jun 26;771:145407. Epub 2021 Jan 26.

College of Veterinary Medicine, Northeast Agricultural University; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Harbin 150030, China. Electronic address:

Hydrogen sulfide (HS) is an environmental contaminant to cause the airway damage. The release of macrophage extracellular traps (METs) is the mechanism of immune protection to harmful stimulation via microRNAs, but excessive METs cause the injury. However, few studies have attempted to interpret the mechanism of an organism injury due to HS via METs in chickens. Here, we investigated the transcriptome profiles, pathological morphologic changes and METs release from chicken trachea after HS exposure. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that 10 differentially expressed genes were related to the METs release, the MAPK and insulin signaling pathways. Morphological and immunofluorescence analysis showed that HS caused airway injury and MET release. HS activated the targeting effect of miRNA-15b-5p on activating transcription factor 2 (ATF2). Western blotting and real time quantitative PCR results showed that HS down-regulated the levels of dual specificity protein phosophatase1 (DUSP1) but up-regulated p38 MAP Kinase (p38) in the MAPK signal pathway. And the expression of phosphoinositide-dependent protein kinase 1 (PDK1), serine/threonine kinase (Akt), and protein kinase ζ subtypes (PKCζ) in the insulin signal pathway were increased after HS exposure. These promoted the release of myeloperoxidase (MPO) and degradation histone 4 (H4) to induce the release of METs. Taken together, miR-15b-5p targeted ATF2 to mediate METs release, which triggered trachea inflammatory injury via MAPK and insulin signals after HS exposure. These results will provide new insights into the toxicological mechanisms of HS and environmental ecotoxicology.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145407DOI Listing
June 2021

MAPK/iNOS pathway is involved in swine kidney necrosis caused by cadmium exposure.

Environ Pollut 2021 Apr 13;274:116497. Epub 2021 Jan 13.

College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.

Cadmium (Cd) pollution in the environment could cause toxic damage to animals and humans. MAPK pathways could regulate their downstream inflammatory factors, and plays a crucial role in necrosis. Since the swine kidney tissue is an important accumulation site of Cd and target organ of its toxic damage, but the damage form of Cd to swine kidney and the role of MAPK pathways in it are still not clear, we selected six week old weaned piglets as the research object, and fed a diet supplemented CdCl (20 mg/kg) to establish the model of liver injury induced by Cd. The expressions and phosphorylation of MAPK pathways (ERK, JNK, p38), expression levels of inflammatory factors (TNF-α, NF-κB, iNOS, COX-2 and PTGE) and necrosis related genes (MLKL, RIPK1, RIPK3 and FADD) and heat shock proteins (HSPs) were detected by RT-PCR and Western blot. H.E. staining was used to determine the damage of kidney caused by Cd exposure. The results showed that Cd exposure could activate p38 and JNK pathway phosphorylation, rather than ERK 1/2, up regulated the expressions of inflammatory factors, finally induced programmed necrosis (increasing the expressions of MLKL, RIPK1, RIPK3 and FADD) in swine kidney. Our study elucidated the mechanism of Cd-damage to swine kidney and the relationship among MAPK pathways, inflammatory factors and programmed necrosis in swine.
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http://dx.doi.org/10.1016/j.envpol.2021.116497DOI Listing
April 2021

The complete mitochondrial genome of the assassin bug (Hemiptera: Reduviidae).

Mitochondrial DNA B Resour 2020 Jun 24;5(3):2561-2562. Epub 2020 Jun 24.

Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management College of Pant Protection, China Agricultural University, Beijing, China.

The complete mitochondrial genome (mitogenome) of the assassin bug, , was sequenced and analyzed in the present study. This mitogenome spans 15,644 bp in size with a high A + T content (71.7%), containing 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a putative control region. All protein-coding genes are initiated by ATN codons expect use GTG as start codons and terminated with TAG or TAA, expect use a single T-- residue as the stop codon. All tRNAs have the typical clover-leaf like structures except for . A phylogenetic analysis of and 33 other assassin bugs is also presented using 13 protein-coding genes and 2 rRNA genes. The result supports the monophyly of Harpactorinae and the sister relationship between and .
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http://dx.doi.org/10.1080/23802359.2020.1780988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782933PMC
June 2020

Mechanism of CuSO cytotoxicity in goat erythrocytes after high-level in vitro exposure to isotonic media.

Ecotoxicol Environ Saf 2021 Jan 9;208:111730. Epub 2020 Dec 9.

College of Animal Science, Tarim University, Alar, Xinjiang Uygur Autonomous Region 843300, PR China; Key Laboratory of Tarim Animal Husbandry Technology Corps, Tarim University, Alar, Xinjiang Uygur Autonomous Region 843300, PR China. Electronic address:

Copper (Cu) is a common environmental pollutant in nature. Cu-poisoning can cause liver damage and erythrocytes hemolysis. To evaluate the effect of CuSO poisoning on the morphological and functional characteristics of goat red blood cells. Five 10-14-month-old goats were selected for jugular vein blood sampling to obtain erythrocytes, and then the erythrocytes were processed with different concentrations (0, 10, 20, 30, 40 and 50 μmol/L) of CuSO for 48 h, and 40 μmol/L doses CuSO incubated for different time (12, 24, 36, 48 and 60 h) to process erythrocytes. We observed the changes in erythrocyte morphology through scanning electron microscopy, and detected the antioxidant function and activities of three ATPases. Additionally, biological properties were examined from the perspectives of phospholipids and membrane protein components, permeability fragility, and fluidity in erythrocytes. We found that after CuSO treatment, the antioxidant capacity of erythrocytes decreased, which was manifested as increased MDA content and decreased CuZn-SOD and GSH-Px activities (p < 0.05). In addition, we also found that erythrocyte fluidity decreased, osmotic fragility increased, membrane phospholipid percentage and protein composition changes abnormally, and Na/K-ATPase Mg-ATPase and Ca-ATPase activities decreased (p < 0.05). From the results, it can be concluded that CuSO exposure causes hemolysis of goat erythrocytes through oxidative stress to the structure and function of erythrocytes, showing a dose-time effect.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111730DOI Listing
January 2021

The complete mitochondrial genome of the lychee stinkbug (Hemiptera: Tessaratomidae).

Mitochondrial DNA B Resour 2019 Dec 18;5(1):321-322. Epub 2019 Dec 18.

Department of Entomology and MOA Key Lab of Pest Monitoring and Green Management, College of Plant Protection, China Agricultural University, Beijing, China.

The lychee stinkbug is an important pest which mainly distributed in southern China. In this study, we sequenced and described the complete mitochondrial genome (mitogenome) of , which is the first record in the genus This mitogenome is 15,973 bp long and comprises of 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and a control region. Gene order is identical to that of the putative ancestral arrangement of insects. All protein-coding genes initiate with ATN, expect and use GTG or TTG as start codons and terminate with TAG or TAA, expect and use TA or a single T residue as the stop codon. All tRNAs, ranging from 62 to 74 bp, can be folded into typical clover-leaf structure expect for and . The control region is 1,357 bp long with 73.5% A + T content. The phylogenetic analysis supports the monophyly of Tessaratomidae and the sister relationship between and .
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http://dx.doi.org/10.1080/23802359.2019.1703609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748429PMC
December 2019

IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells.

Eur J Pharmacol 2021 Mar 18;894:173817. Epub 2020 Dec 18.

School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China. Electronic address:

The inflammatory milieu in tumor modulates the resistance to the conventional antitumoral therapies. Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine and a crucial mediator of tumor development, has been targeted as a therapeutic strategy to overcome chemoresistance in the treatment of tumors. The protein levels and nuclear translocation of HIFs (hypoxia-inducible factors), such as HIF-1α, are linked to the drug resistance of tumor cells. However, whether IL-6 promotes the nuclear translocation of HIF-1α and the related mechanism remain to be investigated. We applied two ovarian cancer (OvCa) cell lines, A2780 cells and SKOV3 cells for the in vivo and in vitro studies. We found that IL-6 up-regulates the HIF-1α expression via the signal transducer and activator of transcription 3 (STAT3) signaling under hypoxia in either endogenous or exogenous way, and then we proved that IL-6 enhances the transcriptional activity of HIF-1α via the STAT3 signaling. Further mechanism research revealed that IL-6 promotes the nuclear translocation of HIF-1α through the STAT3 signaling under hypoxia. Proliferation assay and apoptosis assay were applied and proved that IL-6 enhances the chemoresistance of OvCa cells against cisplatin through the upregulation of HIF-1α via the STAT3 signaling in vitro. The In vivo studies confirmed the effect of IL-6 in increasing the chemoresistance of OvCa cells against cisplatin through the IL-6/STAT3/HIF-1α loop in the animal models. Our data elucidates the explicit mechanism of IL-6/STAT3/HIF-1α loop in OvCa and also provides new insights into the development of different approaches for the inflammation-induced and hypoxia-induced resistance in tumor therapies.
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http://dx.doi.org/10.1016/j.ejphar.2020.173817DOI Listing
March 2021

Resveratrol relieves chlorothalonil-induced apoptosis and necroptosis through miR-15a/Bcl2-A20 axis in fish kidney cells.

Fish Shellfish Immunol 2020 Dec 10;107(Pt B):427-434. Epub 2020 Nov 10.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China. Electronic address:

Chlorothalonil (CT) is a commonly used fungicide and its excessive application seriously threatens aquatic life and human health. Resveratrol (RSV) is a natural polyphenol and can be used as a therapeutic and preventive agent for the treatment of various diseases. To explore the toxic mechanism of CT exposure on fish kidney cell, as well as the alleviation effect of RSV, we established CT poisoning and/or RSV treatment fish kidney cell models. Ctenopharyngodon idellus kidney (CIK) cell line was treated with CT (5 μg/L) and/or RSV (10 μM) for 48 h. The results showed that CT exposure activated cytochromeP450s (CYPs) including CYP1A1, CYP1B1 and CYP1C, caused malondialdehyde (MDA) accumulation, inhibited glutathione (GSH) levels and glutathione peroxidase (GPX) activities, increased the expression of miR-15a and downregulated BCL2 and TNFα-induced protein 3 (TNFAIP3, A20), triggered mitochondrial pathway mediated apoptosis and receptor interacting serine/threonine kinase (RIP)-dependent necroptosis in CIK cells. However, cell death under CT exposure could be relieved by RSV treatment through inhibiting the expression of CYP1 family genes and restoring miR-15a/BCL2-A20 axis disorders. Overall, we conclude that RSV could relieve CT-induced apoptosis and necroptosis through miR-15a/Bcl2-A20 axis in CIK cells. These results enrich the toxicological mechanisms of the CT and confirm that RSV can be used as a potential antidote for CT poisoning.
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http://dx.doi.org/10.1016/j.fsi.2020.11.007DOI Listing
December 2020

The Arabidopsis zinc finger proteins SRG2 and SRG3 are positive regulators of plant immunity and are differentially regulated by nitric oxide.

New Phytol 2021 04 7;230(1):259-274. Epub 2020 Nov 7.

Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3BF, UK.

Nitric oxide (NO) regulates the deployment of a phalanx of immune responses, chief among which is the activation of a constellation of defence-related genes. However, the underlying molecular mechanisms remain largely unknown. The Arabidopsis thaliana zinc finger transcription factor (ZF-TF), S-nitrosothiol (SNO) Regulated 1 (SRG1), is a central target of NO bioactivity during plant immunity. Here we characterize the remaining members of the SRG gene family. Both SRG2 and, especially, SRG3 were positive regulators of salicylic acid-dependent plant immunity. Analysis of SRG single, double and triple mutants implied that SRG family members have additive functions in plant immunity and, surprisingly, are under reciprocal regulation. SRG2 and SRG3 localized to the nucleus and functioned as ethylene-responsive element binding factor-associated amphiphilic repression (EAR) domain-dependent transcriptional repressors: NO abolished this activity for SRG3 but not for SRG2. Consistently, loss of GSNOR function, resulting in increased (S)NO concentrations, fully suppressed the disease resistance phenotype established from SRG3 but not SRG2 overexpression. Remarkably, SRG3 but not SRG2 was S-nitrosylated in vitro and in vivo. Our findings suggest that the SRG family has separable functions in plant immunity, and, surprisingly, these ZF-TFs exhibit reciprocal regulation. It is remarkable that, through neofunctionalization, the SRG family has evolved to become differentially regulated by the key immune-related redox cue, NO.
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http://dx.doi.org/10.1111/nph.16993DOI Listing
April 2021

Protective effects of selenium yeast against cadmium-induced necroptosis via inhibition of oxidative stress and MAPK pathway in chicken liver.

Ecotoxicol Environ Saf 2020 Dec 23;206:111329. Epub 2020 Sep 23.

College of Animal Science, Tarim University, Alar, Xinjiang Uygur Autonomous Region, 843300, China. Electronic address:

The aim of the study was to investigate the protective effects of selenium yeast (SeY) against necroptosis triggered by Cd via inhibition of oxidative stress and MAPK pathway in the liver of chicken. Two hundred 120-day-old layers were randomly divided into four groups and raised for 120 days. The histopathological examination showed that necrosis characteristics were observed in Cd-exposed chicken livers. The exposure of Cd significantly reduced the activities of SOD, GSH-Px and CAT while improving MDA level in both serum and liver of chickens (P < 0.05), and induced oxidative stress. The MLKL, Rip1, RIP3, ERK, JNK and P38 mRNA expression of Cd group were significantly higher than other three groups (P < 0.01), and those in the Se + Cd group were significantly higher than control group and Se group (P < 0.01). However, the mRNA expression level of caspase8 of Cd was significantly lower than other three groups (P < 0.01), and that in the Se + Cd group was significantly higher than control group and Se group (P < 0.01), so the supplement of SeY could improve these situations. Similar results were also detected at the protein level. The results of the present study indicated that Cd could induce oxidative stress, activate MAPK pathway and evoke necroptosis damage in chicken livers, whereas SeY had protective effects in preventing this kind of Cd-induced injury by inhibition of oxidative stress and down-regulation MAPK pathway.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111329DOI Listing
December 2020

Chlorpyrifos induces the apoptosis and necroptosis of L8824 cells through the ROS/PTEN/PI3K/AKT axis.

J Hazard Mater 2020 11 15;398:122905. Epub 2020 May 15.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China. Electronic address:

Excessive chlorpyrifos (CPF) in the environment causes toxicity to nontarget organisms by triggering oxidative stress. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) plays an important role in controlling apoptosis and necrosis by negatively regulating the phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) pathway. However, the effects of different concentrations of CPF on grass fish liver cell injury and the role of the ROS/PTEN/PI3K/AKT axis remain poorly understood. In this study, L8824 cells treated with different concentrations of CPF (0, 40, 60, or 80 μM) were used as the research object. The results showed that the median inhibitory concentration (IC50) was 112.226 μM. As the CPF concentrations increased, the ROS and MDA levels increased, and the T-AOC levels and SOD/GPx/GST activities decreased. As PTEN expression increased, PI3K/AKT, BCL-2, and Caspase-8 expression dramatically decreased. Conversely, RIPK1/RIPK3/MLKL and Bax/Cyt-c/Caspase-3 expression increased. Additionally, necroptosis increased in a dose-dependent manner, while apoptosis first increased and then decreased. In conclusion, our study showed that CPF could trigger oxidative stress and induce apoptosis and necroptosis in fish liver cells by regulating the ROS/PTEN/PI3K/AKT axis, and the type of damage induced was dose-dependent. These results are meaningful for toxicological studies of CPF and efforts to protect the ecosystem.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122905DOI Listing
November 2020

The antagonistic effect of selenium on lead-induced necroptosis via MAPK/NF-κB pathway and HSPs activation in the chicken spleen.

Ecotoxicol Environ Saf 2020 Nov 3;204:111049. Epub 2020 Aug 3.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China. Electronic address:

Recent studies identified a novel programmed and regulated cell death that was characterized by a necrotic cell death morphology, termed necroptosis. Lead (Pb) is known as a persistent inorganic environmental pollutant that affects the health of humans and animals worldwide. However, there are no detailed reports of Pb-induced necroptosis of immune tissue. Selenium (Se) is a trace element that antagonizes the toxicity of heavy metals. Here, chickens were randomly divided into four groups, treated with Pb ((CHOO)Pb, 150 mg/kg) and/or Se (NaSeO, 2 mg/kg), aim to study the effect and mechanism of necroptosis in Pb-induced spleen injury and the antagonistic effects of Se on Pb toxicity. Our results showed that Pb exposure evidently increased the accumulation of Pb in spleen and caused necroptosis by upregulating the expression of RIP1, RIP3 and MLKL, and decreasing Caspase8 expression. Meanwhile, Pb treatment inhibited the activities of SOD, GPX, and CAT, caused the accumulation of NO and MDA, and induced oxidative stress, which promoted the expression of MAPK/NF-κB pathway genes (ERK, JNK, P38, NF-κB and TNF-α) and activated HSPs (HSP27, HSP40, HSP60, HSP70 and HSP90). However, the increased content of Pb in spleen and Pb-caused necroptosis were inhibited by Se cotreatment. Overall, we conclude that Se can prevent Pb-induced necroptosis by restoring antioxidant functions and blocking the MAPK/NF-κB pathway and HSPs activation in chicken spleen.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111049DOI Listing
November 2020

The imbalance of Th1/Th2 triggers an inflammatory response in chicken spleens after ammonia exposure.

Poult Sci 2020 Aug 12;99(8):3817-3822. Epub 2020 Jun 12.

Department of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China. Electronic address:

Ammonia is a hazardous environmental pollutant that can be harmful to animal health. In this study, we aimed to evaluate the effect of ammonia exposure on broiler chicken spleens. We randomly divided one hundred twenty 1-day-old broiler chickens into 3 groups and raised them with exposure to different ammonia concentrations (low, middle, and high); at 42 D of age, the chicken spleens were extracted. We observed histopathologic changes in spleen tissues by microscopy and measured the expression of Th1/Th2 secreted cytokines (interleukin [IL]-1β, IL-2, IL-4, IL-6, IL-10, interferon-γ [IFN-γ], tumor necrosis factor-α) by RT-PCR. We also measured the expression of nuclear receptor-κB (NF-κB) pathway-related genes (cyclooxygenase-2 [COX-2], nitric oxide synthase [iNOS], and prostaglandin synthetase [PGE]) in spleens by RT-PCR and Western blot analysis. Histopathologic observations indicated that the spleen tissues were seriously injured in the high ammonia concentration group. There was abnormal cytokine expression, including increased IL-4, IL-6, and IFN-γ and decreased IL-2, which indicated an imbalance in the Th1/Th2 response. The proinflammatory factors such as NF-κB, COX-2, iNOS, and PGE were upregulated in the high ammonia group. In conclusion, this study illustrated that ammonia exposure led to a Th1/Th2 immune imbalance and triggered the NF-κB pathway, causing inflammatory damage to the spleen.
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http://dx.doi.org/10.1016/j.psj.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598003PMC
August 2020

Selenium-deficient diet induces necroptosis in the pig brain by activating TNFR1 via mir-29a-3p.

Metallomics 2020 08;12(8):1290-1301

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China.

Selenium (Se) deficiency is one of the crucial factors related to nervous system disease and necroptosis. MicroRNAs (miRNAs) play vital roles in regulating necroptosis. However, the mechanism of Se deficiency-induced necroptosis in the pig brain tissue and the role that miRNAs play in this process are unclear. Therefore, in this study, in vitro and pig models of Se deficiency were replicated, and electron microscopy, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays were performed. The results showed that brain cells typically undergo necrotic changes, and that Se deficiency suppresses mir-29a-3p, which increases the levels of TNFRSF1A (TNFR1). Subsequently, a distinct increase in the necroptosis markers (RIPK1, RIPK3, and MLKL) and an evident decrease in caspase 8 was observed. And the expression of 10 selenoproteins was decreased. Moreover, the in vitro experiments showed that the expression of mir-29a-3p decreased as the Se content in the medium decreased and the application of an mir-29a-3p inhibitor increased the number of necrotic cells and the accumulation of ROS, and these effects were inhibited by necrostatin-1 (Nec-1) and N-acetyl-cysteine (NAC), respectively. Taken together, we proved that Se deficiency induced necroptosis both in vitro and in vivo through the targeted regulation of TNFR1 by mir-29a-3p in the pig brain.
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http://dx.doi.org/10.1039/d0mt00032aDOI Listing
August 2020

Cadmium-induced oxidative stress promotes apoptosis and necrosis through the regulation of the miR-216a-PI3K/AKT axis in common carp lymphocytes and antagonized by selenium.

Chemosphere 2020 Nov 11;258:127341. Epub 2020 Jun 11.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, PR China. Electronic address:

Cadmium (Cd) is a primary environmental pollutant which causes the immune dysfunction of aquatic animals. MicroRNAs (miRNAs) play a key role in programmed necrosis and apoptosis of immune organs. Selenium (Se), known as an important element, can antagonize Cd toxicity in birds, but the impact of Se on common carps (Cyprinus carpio) has not been reported. To investigate the Cd-induced immunotoxicity mechanism mediated by miR-216a in splenic lymphocytes of common carp and antagonized by Se, we extracted lymphocytes from the spleen and divided them into control group, Se group (10 mol/L of NaSeO), Se + Cd group and Cd group (4 × 10 mol/L of CdCl). After 6 h of incubation, AO/EB staining, Flow cytometry, qPCR and Western blot were performed. The results showed that Cd exposure caused the apoptosis (BAX, Bcl-2, Caspase 3, Caspase 9) and programmed necrosis (RIP, RIP3, MLKL) in lymphocytes, increased the expression of CYP enzymes, glycometabolism-related enzymes and production of ROS, while irritated the oxidative stress (MDA, SOD, CAT and GSH-PX), upregulated the expression of miR-216a which attenuated the levels of PI3K. However, those variations were apparently mitigated in the Se + Cd group. In short, we have proven that Cd activates oxidative stress and miR-216a-PI3K/AKT axis disorder, thus promoting apoptosis and necrosis in lymphocytes. Moreover, Se can antagonize Cd-triggered apoptosis and necrosis in lymphocytes.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127341DOI Listing
November 2020

Bisphenol A regulates cytochrome P450 1B1 through miR-27b-3p and induces carp lymphocyte oxidative stress leading to apoptosis.

Fish Shellfish Immunol 2020 Jul 11;102:489-498. Epub 2020 May 11.

College of Veterinary Medicine, Northeast Agricultural University, China. Electronic address:

Bisphenol A (BPA) is an industrial raw material widely used in water bottles, medical devices and food packaging, and is now ubiquitous in the environment. However, the effects of BPA on the toxicity of fish lymphocytes and the roles of microRNA (miRNA) in this process remain poorly understood. To explore the mechanism, we exposed carp spleen lymphocytes to BPA of 1, 5 and 10 nM for 24 h. The results showed that BPA induced carp lymphocyte apoptosis. BPA inhibited the expression of miR-27b-3p mRNA, thereby increasing the expression of cytochrome P450 1B1, increasing ROS levels, inhibiting SOD, CAT, GSH-PX activity, GSH content, promoting the accumulation of NOS and MDA. At the same time, BPA activated the mitochondrial apoptosis pathway, inhibited the expression of BCL-2, and promoted the expression of CytC, BAX, Caspase-9 and Caspase-3. Dual luciferase reporter system showed CYP1B1 is the target genes of miR-27b-3p and negatively regulated by it. Overexpression of miR-27b-3p partially reversed oxidative stress and apoptosis of carp spleen lymphocytes induced by BPA stimulation. Taken together, BPA exposure can target up regulate CYP1B1 expression by down regulating miR-27b-3p expression, thus causing oxidative stress and inducing apoptosis of carp spleen lymphocytes through mitochondrial pathway. Our study will provide theoretical basis for immunotoxicology mechanism research and environmental protection of BPA in fish.
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http://dx.doi.org/10.1016/j.fsi.2020.05.009DOI Listing
July 2020

Cooperative application of transcriptomics and ceRNA hypothesis: LncRNA-107052630/miR-205a/G0S2 crosstalk is involved in ammonia-induced intestinal apoptotic injury in chicken.

J Hazard Mater 2020 09 18;396:122605. Epub 2020 Apr 18.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China. Electronic address:

Ammonia (NH), as a harmful gas from agricultural production, plays an important role in air pollution, such as haze. Although numerous researchers have paid attention to health damage through NH inhalation, the exhaustive mechanism of NH induced intestinal toxicity remains unclear. A genes crosstalk named competing endogenous RNAs (ceRNA) can explain many regulatory manners from the molecular perspective. However, few studies have attempted to interpret the injury mechanism of air pollutants to the organism via ceRNA theory. Here, we thoroughly investigated the lncRNA-associated-ceRNA mechanism in jejunum samples from a 42-days-old NH-exposed chicken model through deep RNA sequencing. We observed the occurrence of apoptosis in jejunum, obtained 46 significantly dysregulated lncRNAs and 30 dysregulated miRNAs, and then constructed lncRNA-associated-ceRNA networks in jejunum. Importantly, a network regulating G0S2 in NH-induced apoptosis was discovered. Research results showed that G0S2 was upregulated in jejunum of NH-exposed group and was associated with activation of the mitochondrial apoptosis pathway. G0S2 antagonized the anti-apoptotic effect of Bcl2, which could be reversed by miR-205a. Meanwhile, lncRNA-107052630 acted as ceRNA to affect G0S2 function. These data provide new insight for revealing the biological effect of NH toxicity, as well as the environmental research.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122605DOI Listing
September 2020

Selenium Prevents Lead-Induced Necroptosis by Restoring Antioxidant Functions and Blocking MAPK/NF-κB Pathway in Chicken Lymphocytes.

Biol Trace Elem Res 2020 Dec 12;198(2):644-653. Epub 2020 Apr 12.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.

Recent studies have identified a new existence of a genetically programmed and regulated cell death characterized by necrotic cell death morphology, termed necroptosis. Lead (Pb) is a ubiquitously distributed environmental pollutant that is highly toxic to animals and human beings. However, no detailed report has been conducted on the necroptosis in lymphocytes caused by Pb. Selenium (Se), a trace element in the body, has been shown to exert cytoprotective effect in numerous pathological injury caused by heavy metals. Here, lymphocytes isolated from chicken spleen were divided into four groups, control group, Se group, Pb group, and Pb + Se co-treatment group to investigate the potential mechanism in the necroptosis triggered by Pb and in the antagonistic effect of Se on Pb toxicity. Flow cytometry analysis and AO/EB staining showed Pb caused typical necrosis characteristics in the lymphocytes. The expression of RIP1, RIP3, and MLKL was increased, whereas the level of caspase 8 was declined in Pb group, which proved the occurrence of necroptosis. Meanwhile, Pb exposure disrupted the antioxidant enzyme (SOD, GSH-Px, and CAT) balance, promoted the expression of MAPK/NF-κB pathway factors (ERK, JNK, p38, NF-κB, and TNF-α), and activated HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90). However, those Pb-induced changes were significantly alleviated in Se + Pb group. Our study revealed that Pb could trigger lymphocyte necroptosis through MAPK/NF-κB pathway activated by oxidative stress and that Se could antagonize Pb-induced necroptosis in chicken lymphocytes.
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http://dx.doi.org/10.1007/s12011-020-02094-yDOI Listing
December 2020

Pathogenic Activation of Mesenchymal Stem Cells Is Induced by the Disease Microenvironment in Systemic Sclerosis.

Arthritis Rheumatol 2020 08 14;72(8):1361-1374. Epub 2020 Jul 14.

Royal Free Hospital Campus and University College London Medical School, London, UK.

Objective: In systemic sclerosis (SSc), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic MSCs are present in SSc skin and to examine whether exposure to the disease microenvironment activates MSCs and leads to transdifferentiation.

Methods: Skin biopsy material from patients with recent-onset diffuse SSc was examined by collagenase spread of 1-mm-thick surface-parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose-derived MSCs from healthy controls were treated with dermal blister fluid (BF) from patients with diffuse SSc and profiled by next-generation sequencing, or they were evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel.

Results: MSC-like cells undergoing active metakaryotic division were identified in SSc sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to SSc BF caused selective MSC activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor β, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin-31, enhanced osteogenic commitment (calcinosis).

Conclusion: Dividing MSC-like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state.
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http://dx.doi.org/10.1002/art.41267DOI Listing
August 2020

Glyphosate induces lymphocyte cell dysfunction and apoptosis via regulation of miR-203 targeting of PIK3R1 in common carp (Cyprinus carpio L.).

Fish Shellfish Immunol 2020 Jun 23;101:51-57. Epub 2020 Mar 23.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China. Electronic address:

Glyphosate is a widely used pesticide worldwide. The problem surrounding glyphosate is worth investigating, especially with its increased use, and an increasing number of studies have found that the toxic effect of glyphosate is objective. MiR-203 was seldom found in fish diseases or glyphosate researches. This article aims to explore the effect of miR-203 on carp lymphocytes during glyphosate exposure. Therefore, acridine orange/ethidium bromide (AO/EB) and flow cytometry were carried out to evaluate apoptosis, and we also detected CYPs (CYP1A1, CYP1B1, CYP1C), cytokine secretion (IL-1β, IL-8, IL-10, IFN-γ, TNF-α), inflammatory factors (NF-κB, cox-2), and the expression of miR-203 and the PI3K/AKT pathway by RT-PCR and Western blot analyses. Our results demonstrated that glyphosate exposure could induce lymphocyte apoptosis via regulation of miR-203 targeting of PI3K/AKT, which was accompanied by CYPs activation, abnormal cytokine expression and an inflammatory response. These results show that glyphosate is not nontoxic to fish and provide new insights for the usage of glyphosate as an herbicide in the future.
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http://dx.doi.org/10.1016/j.fsi.2020.03.047DOI Listing
June 2020

Selenium deficiency exacerbates LPS-induced necroptosis by regulating miR-16-5p targeting PI3K in chicken tracheal tissue.

Metallomics 2020 04 3;12(4):562-571. Epub 2020 Mar 3.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China.

Multiple tissue necrosis is one of the morphological features of selenium deficiency-mediated injury. MicroRNA (miRNA) participates in the occurrence and development of necroptosis by regulating target genes. Necroptosis is a programmed form of necrosis, and it is closely related to lipopolysaccharide (LPS)-induced injury. Our aim was to investigate whether Se deficiency can promote tracheal injury caused by LPS through miRNA-induced necroptosis. By establishing models of tracheal injury in Se-deficient chickens, we verified the targeting relationship between chicken-derived miR-16-5p and PI3K through bioinformatics, qRT-PCR and WB analyses, and we measured the changes in the expression of genes related to the PI3K/AKT pathway, RIP3/MLKL pathway and MAPK pathway and of heat shock proteins. Under the condition of Se deficiency, the following results were observed: PI3K/AKT expression decreased with the upregulation of miR-16-5p, the expression of necroptosis-related factors (TNF-α, RIP1, FADD, RIP3 and MLKL) increased, and the expression of Caspase 8 significantly decreased (p < 0.05). Light microscopy observations indicated that cell necrosis was the main pathological change due to Se deficiency injury in the tracheal epithelium. The MAPK pathway was activated, and HSP expression was upregulated, indicating that the MAPK pathway and HSPs are both involved in Se deficiency-mediated necroptosis. In addition, Se deficiency promoted the expression of necroptosis-related genes in LPS-treated chickens (p < 0.05), and the pathological changes of cell necrosis were more obvious. In conclusion, we demonstrated that Se deficiency regulates the miR-16-5p-PI3K/AKT pathway and exacerbates LPS-induced necroptosis in chicken tracheal epithelial cells by activating necroptosis-related genes.
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http://dx.doi.org/10.1039/c9mt00302aDOI Listing
April 2020

The proteomic profiling of multiple tissue damage in chickens for a selenium deficiency biomarker discovery.

Food Funct 2020 Feb;11(2):1312-1321

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China. and Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, P. R. China.

Over the past decades, substantial advances have been made in both the early diagnosis and accurate prognosis of numerous cancers because of the impressive development of novel proteomic strategies. Selenium (Se) is an essential trace element in humans and animals. Se deficiency could lead to Keshan disease in humans, mulberry heart disease in pigs and damage of tissues including cardiac injury, apoptosis in the liver, reduction in the immune responses in spleen and cerebral lesions in chickens. However, it is well know that plasma biomarkers are not specific and also show alterations in various diseases including those caused by Se deficiency. Therefore, new definition biomarkers are needed to improve disease surveillance and reduce unnecessary chicken losses due to Se deficiency. To identify new biomarkers for Se deficiency, we performed exploratory heart, liver, spleen, muscle, vein, and artery proteomic screens to further validate the biomarkers using Venn analysis, GO enrichment, heatmap analysis, and IPA analysis. Based on the bioinformatics methods mentioned above, we found that differentially expressed genes and proteins are enriched to the PI3K/AKT/mTOR signal pathway and insulin pathway. We further used western blot to detect the expression of proteins related to the two pathways. Results showed that the components of the PI3K/AKT/mTOR signal pathway were definitely decreased in heart, liver, spleen, muscle, vein and artery tissues in the Se deficient group. Expression IGF and IGFBP2 of the insulin pathway were differentially increased in the heart, liver, and spleen in Se deficient group samples and decreased in muscle and artery. In conclusion, 5 proteins, namely PI3K, AKT, mTOR, IGF, and IGFBP2, were differentially expressed, which could be potentially useful Se deficient biomarkers. In the present study, proteomic profiling was used to elucidate protein biomarkers that distinguished Se deficient samples from the controls, which might provide a new direction for the diagnosis and targeted treatment induced by Se deficiency in chickens.
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http://dx.doi.org/10.1039/c9fo02861gDOI Listing
February 2020

The Antagonistic Effects of Selenium Yeast (SeY) on Cadmium-Induced Inflammatory Factors and the Heat Shock Protein Expression Levels in Chicken Livers.

Biol Trace Elem Res 2020 Nov 3;198(1):260-268. Epub 2020 Feb 3.

College of Animal Science, Tarim University, Alar, 843300, Xinjiang Uygur Autonomous Region, China.

Cadmium (Cd) is a ubiquitous toxic heavy metal in the natural environment that can cause multiple organ damage to the bodies of animals and humans. Selenium yeast (SeY) is a kind of organic selenium (Se) that has a very strong function against Cd-induced injury to tissues or organs. The aim of the current study was to investigate the roles of inflammatory factors and heat shock proteins (HSPs) in inflammatory injury triggered by Cd and to analyze the protective effects of SeY on Cd-induced damnification in the livers of chickens. Two hundred 120-day-old layers were randomly divided into four groups and raised on a conventional diet, or with Se (0.5 mg/kg SeY), Cd (150 mg/kg CdCl), or Se + Cd (0.5 mg/kg SeY and 150 mg/kg CdCl) in their basic diets for 120 days. Then, the liver histopathology, production of nitric oxide (NO), activity of inducible NO synthase (iNOS), and mRNA and protein expression levels of inflammatory factors (iNOS, NF-κB, TNF-α, and PTGE) and heat shock proteins (HSPs 27, 40, 60, 70, and 90) were examined. The results showed that exposure to Cd obviously increased Cd accumulation, NO production, iNOS activity, inflammatory factor, and HSP mRNA and protein expression levels and further caused an inflammatory response. Supplementation with SeY had an antagonistic effect on Cd-induced inflammatory injury in chicken livers. Thus, the present study suggests that SeY can be taken as a potential therapeutic for Cd-induced liver inflammatory injury in chickens.
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http://dx.doi.org/10.1007/s12011-020-02039-5DOI Listing
November 2020

Avermectin inhibits neutrophil extracellular traps release by activating PTEN demethylation to negatively regulate the PI3K-ERK pathway and reducing respiratory burst in carp.

J Hazard Mater 2020 05 11;389:121885. Epub 2019 Dec 11.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, HaRbin 150030, PR China. Electronic address:

Excessive residual avermectin (AVM) in the environment can have toxic effects on non-target organisms. AVM can exert immunotoxicity by inducing genomic demethylation, but its effect on neutrophil extracellular traps (NETs) release in carp is unclear. In this study, carp neutrophils were pretreated with 5 μg/L AVM or 4 μM DNA demethylation inhibitor (aurintricarboxylic acid, ATA), alone or in combination, and then treated with 4 μM phorbol 12-myristate 13-acetate (PMA) to stimulate NETs release. The results showed that exposure of carp neutrophils to AVM significantly suppressed NETs release and MPO expression, increased ROS production, and dramatically reduced PMA-induced cellular respiratory burst. In addition, AVM could bind to the MBD2 molecule, markedly upregulate MBD2 expression to cause demethylation, and clearly activate PTEN expression, thereby inhibiting the expression of PI3K, AKT, Raf, MEK, and ERK. However, these effects were alleviated by ATA. In conclusion, our study showed that AVM could inhibit NETs release in carp by inducing demethylation of PTEN to negatively regulate NETs synthesis pathways and reducing respiratory burst level. Our findings clarify the mechanism of AVM immunotoxicity to fish and are of great significance for efforts to protect the ecological environment and human health.
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http://dx.doi.org/10.1016/j.jhazmat.2019.121885DOI Listing
May 2020

Ammonia regulates chicken tracheal cell necroptosis via the LncRNA-107053293/MiR-148a-3p/FAF1 axis.

J Hazard Mater 2020 03 22;386:121626. Epub 2019 Nov 22.

College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China. Electronic address:

Ammonia (NH) is a known harmful gas that causes injury to the respiratory system. Ammonia also exists in haze, forming secondary organic aerosols. However, the specific damage caused by NH in chicken trachea has not been determined. The regulatory mechanism of ceRNA and its multiple roles have been proposed in many pathomechanisms; therefore, we investigated the functional role of ceRNA in chicken trachea after NH inhalation. Broiler chicken trachea exposed to NH was selected as the research object. The pathological ultrastructure was observed by transmission electron microscopy. Transcriptome analyses were applied and referenced, and lncRNA-107053293 and miR-148a-3p and FAF1 were selected. A dual-luciferase reporter assay verified the target relationship. Real-time quantitative PCR (RT-PCR) and western blotting were performed to examine the expression levels of necroptosis genes, such as RIPK1, RIPK3, MLKL, caspase 8, and FADD. Our results indicated that lncRNA-107053293 regulated necroptosis by acting as a competing endogenous RNA of miR-148a-3p. FAF1, as a gene target of miR-148a-3p, also affects necroptosis.
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http://dx.doi.org/10.1016/j.jhazmat.2019.121626DOI Listing
March 2020

GPx1-mediated DNMT1 expression is involved in the blocking effects of selenium on OTA-induced cytotoxicity and DNA damage.

Int J Biol Macromol 2020 Mar 29;146:18-24. Epub 2019 Nov 29.

College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China. Electronic address:

Ochratoxin A (OTA) is a potent nephrotoxin. Selenium (Se) is an essential micronutrient for humans and animals, and plays a key role in antioxidant defense. To date, little is known about the effect of Se on OTA-induced DNA damage. In this study, the protective effects of Se (from selenomethionine) against OTA-induced cytotoxicity and DNA damage were investigated by using PK15 cells as a model. The results showed that OTA at 4.0 μg/mL induced cytotoxicity and DNA damage. Se at 0.5, 1, 2 and 4 μM significantly blocked OTA-induced cytotoxicity and DNA damage. Furthermore, Se blocked the increases of DNMT1, DNMT3a and HDAC1 mRNA and protein expression, reversed the decreases of glutathione peroxidase 1 (GPx1) mRNA and protein expression, and promoted the increases of SOCS3 mRNA and protein expression induced by OTA. Overexpression of GPx1 by pcDNA3.1-GPx1 inhibited the OTA-induced DNMT1 expression, promoted OTA-induced SOCS3 expression, and prevented the OTA-induced cytotoxicity and DNA damage. In contrast, knock-down of GPx1 by using a GPx1-specific siRNA had the opposite effects. The results suggest that GPx1-mediated DNMT1 expression is involved in the blocking effects of selenium on OTA-induced cytotoxicity and DNA damage.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.11.221DOI Listing
March 2020

Selenium Deficiency Induces Inflammation via the iNOS/NF-κB Pathway in the Brain of Pigs.

Biol Trace Elem Res 2020 Jul 20;196(1):103-109. Epub 2019 Nov 20.

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.

Selenium (Se) is an essential trace element to maintain homeostasis in humans and animals. The aim of the present study was to clarify the mechanism of Se deficiency-induced inflammation in the pig's brain. Twenty-four healthy pigs were randomly divided into two groups (n = 12/group): control group (group C) was fed diet with 0.3 mg/kg inorganic Se, and Se-deficient group (group L) was fed diet with 0.007 mg/kg inorganic Se. At the 90th day of the experiment, the histology in the pig's brain was observed by the microscope, the NO levels and iNOS activity were assayed, and the mRNA and protein expression levels of inflammatory cytokines (iNOS, COX-2, NF-κB, and PTGEs) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) were detected by real-time quantitative PCR and Western blot. Compared with group C, both of NO levels and iNOS activity were increased in group L, and the mRNA and protein expression levels of inflammatory cytokines (iNOS, COX-2, NF-κB, and PTGEs) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) were also upregulated; histological observation displayed inflammatory response in the brain of pig. In summary, diet with Se deficiency can activate the iNOS/NF-κB pathway to upregulate the expression of inflammatory cytokines, thereby leading to inflammatory lesions in the pig's brain, and HSPs are involved in the compensatory regulation of inflammation. This study provides a reference for the prevention of pig brain inflammation from the perspective of nutrition.
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http://dx.doi.org/10.1007/s12011-019-01908-yDOI Listing
July 2020

Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model.

Eur J Vasc Endovasc Surg 2020 Jan 12;59(1):117-127. Epub 2019 Nov 12.

Royal Free Vascular, Division of Surgery and Interventional Science, Royal Free Campus, UCL, London, UK.

Objective: Diabetes mellitus has reached epidemic proportions. Foot ulceration is a multifactorial complication of diabetes associated with marked morbidity and mortality. Innate immune Toll-like receptor 4 (TLR4) mediated inflammation has been implicated in the systemic pathogenesis of diabetes and may contribute to impairment of wound healing. This study investigates the effect of high glucose and hypoxic conditions on TLR4 activation and signalling in vitro and in vivo.

Methods: Fibroblasts cultured at physiological glucose concentration (5.5 mM) were exposed to glucose concentrations from 0 mM to 25 mM, with duplicates placed in a hypoxic chamber. TLR4 inhibition was assessed in the 25 mM glucose groups. Diabetes was induced in wild type (WT) and TLR4 knockout (KO) C57BL/6 mice by intraperitoneal injection of low dose streptozocin (STZ). Hindlimb ischaemia was induced by femoral artery ligation four weeks post streptozocin, and a full thickness 4 mm skin wound inflicted below the knee. Wound healing was assessed via digital planimetry on days 3, 7, and 14 post surgery.

Results: Hypoxic and high glucose (25 mM) conditions led to an increase in TLR4 protein expression, apoptosis, and interleukin (IL)-6 release. Inhibition with a TLR4 neutralising antibody and specific TLR4 antagonist ameliorated the effects of high glucose and ischaemia (p < .05). In vivo, wound healing was significantly impaired in the diabetic ischaemic group at day 14 (p < .05). Diabetic ischaemic wounds in TLR4 KO mice exhibited significantly improved healing rates compared with those in WT mice at all time points.

Conclusion: Hypoxia stimulates upregulation of TLR4 protein expression and this effect is exaggerated by hyperglycaemia. In TLR4 KO mice, there is a significant improvement in the healing of diabetic ischaemic wounds compared with WT. It is suggested that a synergistic effect between hypoxia and hyperglycaemia impairing wound healing exists, through TLR4 mediated inflammation.
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http://dx.doi.org/10.1016/j.ejvs.2019.06.018DOI Listing
January 2020